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J. Biol. Chem., Vol. 280, Issue 27, 25305-25312, July 8, 2005

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Glutathione Redox State Regulates Mitochondrial Reactive Oxygen Production^*

Dongxiao Shen, Timothy P. Dalton, Daniel W. Nebert, and Howard G. Shertzer

From the Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P. O. Box 670056, Cincinnati, Ohio 45267-0056

Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is poorly understood. Following one dose of TCDD (5 µg/kg body weight), mitochondrial succinate-dependent production of superoxide and H₂O₂ in mouse liver doubled at 7–28 days, then subsided by day 56; concomitantly, levels of GSH and GSSG increased in both cytosol and mitochondria. Cytosol displayed a typical oxidative stress response, consisting of diminished GSH relative to GSSG, decreased potential to reduce protein-SSG mixed disulfide bonds (type 1 thiol redox switch) or protein-SS-protein disulfide bonds (type 2 thiol redox switch), and a +10 mV change in GSSG/2GSH reduction potential. In contrast, mitochondria showed a rise in reduction state, consisting of increased GSH relative to GSSG, increases in type 1 and type 2 thiol redox switches, and a –25 mV change in GSSG/2GSH reduction potential. Comparing Ahr(–/–) knock-out and wild-type mice, we found that TCDD-induced thiol changes in both cytosol and mitochondria were dependent on the aromatic hydrocarbon receptor (AHR). GSH was rapidly taken up by mitochondria and stimulated succinate-dependent H₂O₂ production. A linear dependence of H₂O₂ productionon thereduction potential for GSSG/2GSH exists between –150 and –300 mV. The TCDD-stimulated increase in succinate-dependent and thiol-stimulated production of reactive oxygen paralleled a four-fold increase in formamidopyrimidine DNA N-glycosylase (FPG)-sensitive cleavage sites in mitochondrial DNA, compared with a two-fold increase in nuclear DNA. These results suggest that TCDD produces an AHR-dependent oxidative stress in mitochondria, with concomitant mitochondrial DNA damage mediated, at least in part, by an increase in the mitochondrial thiol reduction state.

Received for publication, January 4, 2005 , and in revised form, May 2, 2005.

^* This work was supported in part by National Institutes of Health Grants R01 ES10133 (to H. G. S.), R01 ES08147 (to D. W. N), RO1 ES12463 (to T. P. D.), and P30 ES06096 (to T. P. D., D. W. N., and H. G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Environmental Health, 3223 Eden Ave., Cincinnati, OH 45267-0056. Tel.: 513-558-0522; Fax: 513-558-0925; E-mail: shertzhg{at}ucmail.uc.edu.

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